The Broad Challenge Area addressed in this proposal is (03) Biomarker Discovery and Validation, and the Specific Challenge Topic is 03-HL-101. The purpose of this proposal is to improve the accurate and early diagnosis of idiopathic interstitial lung pneumonia (IIP), and to improve the ability to differentiate the subtypes of idiopathic interstitial pneumonias (IIPs). The current diagnostic approach to idiopathic interstitial pneumonias requires comprehensive diagnostic clinical, radiologic, and pathologic testing optimally performed in tertiary academic referral centers by physicians with expertise in this field. Surgical lung biopsy is required, and is associated with additional cost, morbidity, and mortality. Despite these efforts, the diagnosis in some patients remains uncertain. We seek to make an accurate diagnosis of the various subtypes of idiopathic pneumonias early in the course of the disease without the need for surgical lung biopsy, and to make this approach more widely available in the community by developing peripheral blood markers. Our previous work with familial interstitial pneumonia (FIP, defined as >cases of IIP per family) indicates that FIP is phenotypically and genetically heterogeneous, suggesting that multiple genes cause IIP and that these individual genetic variants are likely to be associated with specific molecular signatures that distinguish this group of complex lung diseases. We have phenotyped 160 families with two or more cases of IIP (familial interstitial pneumonia, FIP) and several years ago reported the findings from the initial 111 families. Within our cohort of familial interstitial pneumonia patients (FIP), by screening unaffected family members, we have identified pre-symptomatic subjects with early disease as well as symptomatic, later stage disease thus collecting patients that span the entire spectrum of disease. We used this cohort to develop a molecular signature of FIP in peripheral blood using peripheral blood gene expression profiles. We identified a peripheral blood transcriptome that distinguishes 14 preclinical and symptomatic patients from 11 healthy controls. Thus, we hypothesize that a peripheral blood biomarker or biological signature (gene or protein expression pattern) of idiopathic interstitial pneumonias (IIPs) will simplify and improve the accuracy of diagnosis of IIP and diagnose individuals at an earlier, more treatable, stage of their disease. We plan to identify a biomarker that can identify early stage disease by using our FIP cohort with pre- symptomatic disease, and that has multiple subtypes of IIP. Idiopathic interstitial pneumonia (IIP) represents a broad spectrum of chronic fibrosing lung conditions that can lead to untreatable respiratory failure. While substantial progress has been made in understanding the clinical, radiological, and pathological manifestations of these disorders, it remains difficult for the clinician to diagnose IIP from other types of interstitial lung disease, particularly to identify the different subtypes of IIP The overall goal of the proposed project is to develop and validate molecular signatures in the peripheral blood that serve to refine the diagnostic criteria for this group of complex diseases;once established these molecular signatures of IIP could be tested in future studies to enhance early detection, to predict outcome, and to mould personalized therapeutic strategies. We will create 2 new job positions for this work over the next 2 years, and the potential to create more in the future to develop standardized clinical diagnostic laboratory assays.